Molecular Dynamics Simulations of Angiotensin II in Aqueous and Dimethyl Sulfoxide Environments

Preto, Marco; Melo, André; Maia, Hernâni L. S.; Mavromoustakos, Thomas; Ramos, María J.

doi:10.1021/jp0521048

Cited by 17 publications

(20 citation statements)

References 33 publications

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“…The smaller size of AngII found in simulations and anisotropy measurements may explain its selective binding to AT 1 and AT 2 . The twisted-extended AngII active structure proposed by Marshall and coworkers is similar to the NMR-determined models (Preto, Melo, Maia, Mavromoustakos, & Ramos, 2005) as well as to several clusters sampled in MD. The extended and U-shaped structures proposed for AngII/receptor complexes may also be found in our trajectories.…”

supporting

confidence: 68%

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

DeLeon

Patel

Kuczera

et al. 2012

Journal of Biomolecular Structure and Dynamics

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We present a study of structural analysis and reorientational dynamics of Angiotensin I (AngI) and Angiotensin II (AngII) in aqueous solution. AngI is a decapeptide that acts as a precursor to the octapeptide AngII in the Renin-Angiotensin-Aldosterone system for blood pressure regulation. Experimental structural characterization of these peptides, carried out with circular dichroism and infrared spectroscopy, showed that the angiotensins are mostly disordered but exhibit a measurable population of ordered structures at room temperature. Interestingly, these change from the unordered polyproline-like conformation for AngI to a more compact and ordered conformation for AngII as the length of the peptide is decreased. Anisotropy decay measurements with picosecond time resolution indicate slower overall tumbling and a greater amplitude of internal motion in AngI compared to AngII, consistent with more compact and less flexible structure of the active form of the peptide. To model the microscopic behavior of the peptides, 2-μs molecular dynamics simulation trajectories were generated for AngI and AngII, at 300 K using the OPLS-AA potential and SPC water. The structures sampled in the simulations mostly agree with the experimental results, showing the prevalence of disordered structures, turns, and polyproline helices. Additionally, the computational results predict fewer sampled conformations, tighter side-chain packing and marked increase of Phe8 solvent accessibility upon AngI truncation to AngII. Our combined approach of experiment and extensive computer simulation thus yields new information on the conformational dynamics of the angiotensins, helping provide insight into the structural basis for the potency of AngI relative to AngII.

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supporting

confidence: 68%

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

DeLeon

Patel

Kuczera

et al. 2012

Journal of Biomolecular Structure and Dynamics

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“…It is possible to build mixtures of several components, solvate proteins, and build ordered arrangements as double layers or micelles. [20][21][22][23][24][25][26][27] Further improvements of the package may include macro-input keywords to build the most common systems and more complex unit cells, the parallelization of tasks other than function and gradient evaluation, the improvement of global convergence heuristics, and the development of a graphical user interface, or its incorporation as a plugin into some graphical molecular viewer.…”

Section: Discussionmentioning

confidence: 99%

PACKMOL: A package for building initial configurations for molecular dynamics simulations

et al. 2009

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Abstract:Adequate initial configurations for molecular dynamics simulations consist of arrangements of molecules distributed in space in such a way to approximately represent the system's overall structure. In order that the simulations are not disrupted by large van der Waals repulsive interactions, atoms from different molecules must keep safe pairwise distances. Obtaining such a molecular arrangement can be considered a packing problem: Each type molecule must satisfy spatial constraints related to the geometry of the system, and the distance between atoms of different molecules must be greater than some specified tolerance. We have developed a code able to pack millions of atoms, grouped in arbitrarily complex molecules, inside a variety of three-dimensional regions. The regions may be intersections of spheres, ellipses, cylinders, planes, or boxes. The user must provide only the structure of one molecule of each type and the geometrical constraints that each type of molecule must satisfy. Building complex mixtures, interfaces, solvating biomolecules in water, other solvents, or mixtures of solvents, is straightforward. In addition, different atoms belonging to the same molecule may also be restricted to different spatial regions, in such a way that more ordered molecular arrangements can be built, as micelles, lipid double-layers, etc. The packing time for state-of-the-art molecular dynamics systems varies from a few seconds to a few minutes in a personal computer. The input files are simple and currently compatible with PDB, Tinker, Molden, or Moldy coordinate files. The package is distributed as free software and can be downloaded from

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“…The CHARMm force field27 was applied for the potential energy calculations and a dielectric constant ε=45 has been used to simulate DMSO environment. DMSO provides an amphiphilic medium, thus mimicking the physiological conditions at the receptor binding site 28. 29 Aliskiren was initially minimized with steepest descent and then with Newton–Raphson algorithms using an energy tolerance of 0.001 kcal mol −1 A −1 .…”

Section: Methodsmentioning

confidence: 99%

Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site

Politi

Leonis

Tzoupis

et al. 2011

Molecular Informatics

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Aliskiren is the first orally active, direct renin inhibitor to be approved for the treatment of hypertension. Its structure elucidation and conformational analysis were explored using 1D and 2D NMR spectroscopy, as well as random search and molecular dynamics (MD) simulations. For the first time, MD calculations have also been performed for aliskiren at the receptor site, in order to reveal its molecular basis of action. It is suggested that aliskiren binds in an extended conformation and is involved in several stabilizing hydrogen bonding interactions with binding cavity (Asp32/255, Gly34) and other binding-cavity (Arg74, Ser76, Tyr14) residues. Of paramount importance is the finding of a loop consisting of residues around Ser76 that determines the entrapping of aliskiren into the active site of renin. The details of this mechanism will be the subject of a subsequent study. Additionally molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) free energy calculations for the aliskiren-renin complex provided insight into the binding mode of aliskiren by identifying van der Waals and nonpolar contribution to solvation as the main components of favorable binding interactions.

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Molecular Dynamics Simulations of Angiotensin II in Aqueous and Dimethyl Sulfoxide Environments

Cited by 17 publications

References 33 publications

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

Structure and reorientational dynamics of angiotensin I and II: a microscopic physical insight

PACKMOL: A package for building initial configurations for molecular dynamics simulations

Conformational Properties and Energetic Analysis of Aliskiren in Solution and Receptor Site

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